Introduction: Pathologic complete response (pCR) following neoadjuvant systemic chemotherapy (NAC) serves as a measure of tumor responsiveness and is a recognized surrogate for improved long-term outcomes. Some, but not all, studies have found a positive association between vitamin D (VD) and disease-free survival. We investigated if VD at diagnosis or during chemotherapy impacts pCR following neoadjuvant chemotherapy for operable breast cancer. Methods: Patients from Iowa were eligible if they were enrolled in one of two Iowa registries and had serum from before or during NAC tested for VD. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were considered for this study. VD deficiency was defined as <20 ng/ml. pCR was defined as no residual invasive disease in breast and lymph nodes. Firth-penalized logistic regression multivariable model was used. Results: The final cohort included 144 women. 84.7% of VD levels were obtained before initiation of chemotherapy. There was no difference between the French and Iowa cohorts with regard to age (p=0.20), clinical stage (p=0.22), disease receptor status (HER2+ [Hormone receptor (HR)+ or HR-], HR+/HER2-, and Triple Negative) (p=0.32) and rate of pCR (p=0.34). French women had lower body mass index (mean 24.8 vs 28.8, p<0.01), lower VD levels (mean 21.5 vs 27.5, p<0.01) and underwent lumpectomy instead of mastectomy more frequently (75.3% vs 47.8%, p<0.01) than Iowa women. Only pCR differed between the VD sufficient and deficient groups (Table 1). In multivariate analysis, after adjusting for the effects of cohort, clinical stage, and disease type by receptor status, VD deficiency put a woman at 2.68 times increased odds of not attaining a pCR (95%CI: 1.12-6.41, p=0.03) (Table 2). This variable remained significant with VD deficiency defined as <30 ng/ml and when considering this variable continuously. Conclusion: In this retrospective cohort, VD level before or during NAC was associated with pCR. Prospective trials could elucidate if maintaining VD levels during NAC, a highly modifiable variable, can be utilized to improve cancer outcomes in addition to benefiting other established health outcomes. Table 1: VD Deficient and Sufficient Groups  Vitamin D (ng/ml)   Deficient (< 20)Sufficient (≥ 20)pN 5391 BMIUnderweight-Normal27 (50.9)47 (51.6)0.93 Overweight-Obese26 (49.1)44 (48.4) VD LevelBefore Chemotherapy45 (84.9)77 (84.6)0.96 During Chemotherapy8 (15.1)14 (15.4) GradeG1-224 (47.1)41 (46.1)0.91 G327 (52.9)48 (53.9) Clinical StageI-II37 (69.8)61 (67)0.73 III16 (30.2)30 (33) Receptor StatusHER2+ (HR+ or HR-)12 (22.6)29 (32.2)0.20 HR+/HER2-30 (56.6)37 (41.1)  Triple Negative11 (20.8)24 (26.7) SurgeryBreast Conserving32 (60.4)58 (63.7)0.69 Mastectomy21 (39.6)33 (36.3) pCRNo43 (81.1)53 (58.2)<.01 Yes10 (18.9)38 (41.8) AgeMean (SD)48 (10.9)51 (10.3)0.15 Table 2: Odds of Not Attaining a pCR: Multivariable Results  NOdds Ratio95% CIp-valueCohortIowa661.170.522.630.71 France77Ref   Vitamin D (<20)Deficient532.681.126.410.03 Sufficient90Ref   Clinical StageI-II97Ref    III463.251.308.110.01Receptor StatusHER2+ (HR+ or HR-)411.060.402.810.91 HR+/HER2-675.502.0414.85<0.01 Triple Negative35Ref    Citation Format: Thomas A, Thezenas S, Mott SL, Raman R, Viala M, Pouderoux S, Schroeder MC, Lamy P-J, Jacot W. Vitamin D level impacts odds of pathologic complete response following neoadjuvant therapy in operable breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-24.

Introduction: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved long-term outcomes. Vitamin D (VD) deficiency has been associated with carcinogenesis as well as poorer outcomes in breast cancer (bc) particularly in luminal-type bc. In addition, replacement of VD during adjuvant chemotherapy was found to improve disease-free survival. However, VD deficiency was not associated with pCR following NAC in one series which included patients (pts) with human epidermal growth factor receptor-2 (HER2) negative bc only. We report the relationship between VD deficiency and pCR in a cohort that includes all bc subtypes and report how VD deficiency varied by clinical and pathologic parameters. Methods: Patients (pts) prospectively enrolled in the University of Iowa Breast Molecular Epidemiologic Resource between 2010-14 with invasive bc, receiving at least one cycle of NAC, and who had serum collected at enrollment or during NAC were eligible. VD deficiency was defined as < 20 ng/dl. pCR was defined as no residual invasive disease in breast and lymph nodes. Patients were stratified by their BMI as normal (≤ 25 kg/m2) or overweight-obese (>25 kg/m2). To investigate the relationship between VD, clinical parameters, and NAC outcomes, chi-square, Fisher's exact, and t-tests were used. Results: 73 pts were eligible. 52 (71%) pts had Stage I-II bc. All pts received a combination of taxanes with other agents (Cytoxan, 5FU, Carboplatin, Gemcitabine) with or without an anthracycline or anti-HER 2 therapy. 62/73 (85%) received an anthracycline. 65/73 (89%) received at least 75% of intended NAC. pCR was achieved in 25/73 (34%) pts. VD deficiency was found in 17/73 (23%) pts and was more frequent among overweight-obese pts (Table 1). VD deficiency occurred significantly more often in estrogen receptor (ER)+/progesterone receptor (PR)+/HER2- and ER+ or PR+ bc but not in HER2+ bc. Results suggest VD deficient pts may be at increased odds of not achieving a pCR (OR=3.02, p=0.10). In this cohort, VD deficient pts were at increased odds of having residual disease in the breast (OR=3.76, p=0.05), but not in the nodes (OR=1.43, p=0.53), (Table 2). Conclusion: Being overweight-obese was associated with VD deficiency and may warrant screening in this group. VD deficiency was significantly associated with ER+/PR+/HER2-bc and ER+ or PR+ disease. Notably, these pts are candidates for bone-injuring anti-estrogen agents as part of their overall course of therapy. VD deficiency was not significantly associated with pCR after NAC though a trend was suggested. Table 1: VD and clinical parameters   VD Sufficient VD Deficientp  N=56N=17 Age (mean in years) 52470.16BMI≤2526(46%)3(18%)0.03 >2530(54%)14(82%) Ellis-Ellison grade1-224(43%)7(41%)0.90 332(57%)10(59%) Tumor receptorER+/PR+/HER2-15(27%)10(59%)0.02 ER+ or PR+/HER2+6(11%)3(18%)0.43 ER-/PR-/HER2+10(18%)0(0%)0.10 ER-/PR-/HER2-17(31%)3(18%)0.36 ER+ or PR+29(52%)14(82%)0.02 HER2+16(84%)3(16%)0.53 Table 2: VD and NAC Outcomes   VD SufficientVD Deficientp  N=56N=17 pCRNo34(61%)14(82%)0.10 Yes22(39%)3(18%) Breast Residual DiseaseNo25(45%)3(18%)0.05 Yes31(55%)14(84%) Node Residual DiseaseNo28(50%)7(41%)0.52 Yes28(50%)10(59%)  Citation Format: Raman R, Link BK, Mott SL, Schroeder MC, Thomas A. Vitamin D deficiency in various breast cancer subtypes and its impact on response to neoadjuvant chemotherapy in operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-48.

Introduction: pCR following NAC is associated with improved long term outcomes. Though obesity is associated with chemo-resistance, its impact on pCR is less clear, likely because most studies were unable to account for NAC dose adjustments. An association between taxane dose reduction and BMI has previously been shown in European populations. However, most patients (pts) with increased BMI had doses capped at BSA of 2. We studied the impact of BMI on NAC dosing when treatment is based on actual weight and whether dosing adjustments preferentially impact pCR rate. Methods: Pts prospectively enrolled in the University of Iowa Breast Molecular Epidemiologic Resource from 2010-14 with invasive bc who received at least one cycle of NAC were eligible. Pts were stratified by BMI category: normal (BMI ≤25) or overweight-obese (BMI >25). Planned total dose was calculated based on both dosing and number of cycles. Dose reduction was defined as any decrease in total intended dose. pCR was defined as no residual invasive disease in breast and lymph nodes. To investigate the relationship between BMI, dose reductions, and pCR, chi-square tests and logistic regression models were used. Results: 87 pts were eligible. 22 (26%), 25 (29%) and 51 (59%) of pts had HER2 positive, triple negative and hormone receptor positive bc (HER- or +), respectively. 62 (71%) pts had Stage I-II bc. All pts received a combination of taxanes with other agents (Cytoxan, 5FU, Carboplatin, Gemcitabine) with or without an anthracycline (Adriamycin or Epirubicin) or anti HER 2 therapy (Pertuzumab, Traztuzumab or Lapatinib) and were initially dosed based upon actual body weight. Taxanes were planned at treatment initiation in all pts. Anthracyclines were given to 71 (82%) pts. pCR was achieved in 28 (32%) pts. Association between BMI and NAC dosing are shown in - Table 1: Association between NAC dosing and BMI category NormalOverweight-ObesepN3651  NoYesNoYes Taxane dose reduction30(83%)6(17%)29(57%)22(43%)<0.01Non taxane dose reduction28(78%)8(22%)40(78%)11(22%)0.94 . Relative to normal weight pts, overweight-obese pts were more likely not to achieve a pCR (OR 2.09, CI 0.84-5.21, p=0.11) and have residual disease in the breast alone (OR 2.92, CI 1.18-7.24, p=0.02). Overweight-obese pts with taxane reductions, relative to overweight-obese pts without taxane reductions, were at elevated odds of not achieving a pCR (OR 2.03, CI 0.53-7.73) -. Table 2: Impact of taxance dose reduction on pCR by BMI category  NormalOverweight-Obese  No pCRpCRNo pCRpCRTaxane reductionNo19(63%)11(37%)20(69%)9(31%) Yes2(33%)4(67%)18(82%)4(28%) Interaction between BMI and taxane dose reduction on pCR trended towards significance (p=0.10), a trend not seen for non-taxane drugs. The most common adverse event resulting in taxane dose reduction was neuropathy (10/28 pts). Conclusion: Overweight-obese women experienced significantly higher rates of taxane dose reductions during NAC for bc with initial full-weight dosing. BMI status may modify the effects of taxane dose reduction on the likelihood of not achieving a pCR, Further investigation of this outcome in a larger cohort is warranted. Citation Format: Raman R, Mott SL, Schroeder MC, Thomas A. Impact of body mass index (BMI) and neo-adjuvant chemotherapy (NAC) dosing on pathologic complete response (pCR) in operable breast cancer (bc). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-14.

Introduction: There has been increasing interest in the potential benefit of vitamin D to improve breast cancer outcomes. Pre-clinical studies suggest vitamin D enhances chemotherapy-induced cell death. We previously reported (Thomas A SABCS 2016) that low serum vitamin D levels were associated with not attaining a pathologic complete response (pCR) following breast cancer neoadjuvant chemotherapy (NAC). We report here the impact of vitamin D on survival parameters in an expanded cohort of patients. Methods: Patients from two Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. Survival was defined from the date of diagnosis to the date of relapse (PFS) or date of death (OS). Results: The study included 327 women. Median age was 51 years. Patients presented with HER2+, HR+/HER2- and triple negative (TN) tumors in 28.5%, 43.9% and 27.6% of the cases respectively. In this expanded cohort, vitamin D deficiency remained associated with the odds of not attaining pCR (OR 1.64; 95%CI: 1.02-2.66, p=0.04). Median follow-up was 5.33 years (range 0.5 to 9.8 years). Of these patients, there were 54 relapse and 52 deaths. In multivariate analysis, stage III disease, TN phenotype and the inability to achieve pCR were independently associated with a worse survival (Table 1). Table 1 PFS (Hazard Ratio, 95%CI)pOS (Hazard Ratio, 95%CI)pStage    I - II1 1 III2.78 (1.56 – 4.95)0.0012.82 (1.57 - 5.05)0.001Tumor phenotype    HR+/HER2-1 1 HER2+3.00 (1.28 – 7.06)0.0121.78 (0.76 – 4.08)0.174TN7.37 (3.26 – 16.69)< 0.0016.50 (3.07 – 13.76)< 0.001NAC response    Non-pCR1 1 pCR0.19 (0.08 – 0.45)< 0.0010.22 (0.09 – 0.55)< 0.001Vitamin D    < 20 ng/mL1 1 ≥ 20 ng/mL1.01 (0.57 – 1.78)0.971.03 (0.58 – 1.84)0.92 Vitamin D deficiency was not significantly associated with survival parameters in the general population; however a trend was seen in the TN population regarding the correlation with PFS (90 patients, 5-year PFS 60.4% vs. 72.3%, p=0.18). Conclusion: Vitamin D deficiency is associated with the inability to reach pCR in breast cancer undergoing NAC. A trend for worse survival was seen in the TN subgroup. The strong association between vitamin D deficiency and the inability to reach pCR warrant further evaluation in the TN subgroup. Prospective interventional studies are needed to elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes, particularly in TN breast cancers. Citation Format: Viala M, Chiba A, Thezenas S, Delmond L, Lamy P-J, Mott SL, Schroeder MC, Thomas A, Jacot W. Clinical correlations of serum vitamin D in patients undergoing neoadjuvant systemic therapy and survival outcomes for operable breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-09.

it may be associated with significant acute and long-term side effects. We hypothesized that reductions in dose to the primary target (<69.3 Gy) and elective neck (<50 Gy) would result in similar control and may reduce acute toxicity. Materials/Methods: After IRB approval was obtained, a database of HPV or p16 positive non-metastatic OPSCC patients treated with definitive radiation therapy with or without chemotherapy was queried. Relevant features of patients in high-dose groups and low-dose groups were compared with Fischer Exact test. Locoregional control (LRC), regional control (RC), and overall survival (OS) were calculated from the end of RT and estimated via Kaplan-Meier method and comparisons made via log-rank test. Results: A total of 387 patients were available for analysis with a median follow-up was 33 months. Standard doses of 69.3 Gy (median 70, range 69.3-75.2) were used in 298 patients, and <69.3 Gy (median 66 Gy, range 58-68 Gy) in 89 patients. Standard elective neck doses of 50 Gy (median 56 Gy, range 50-56 Gy) were used in 311 patients and <50 Gy (median 46, range 40-49.6) in 71 patients. Patients in the high-dose range to the primary target or elective neck were more likely to be higher AJCC 8 th edition T stage, N stage, and overall stage (P < .05 for all comparisons). There was no difference in the 3-year LRC comparing <69.3 Gy and 69.3 Gy (95.2% and 91.8% respectively, P Z .67), no difference in the 3-year RC comparing the <50 Gy and 50 Gy arms (94% vs 90% respectively P Z .41). There was no difference in 3-year OS for both <69.3 Gy (95.3% and 87.3%, respectively, P Z .13) and <50 Gy (95.6% and 87.9%, respectively, P Z .20). When stratifying by AJCC 8 th edition T, N, overall stages, or concurrent chemotherapy, there was no difference in LRC, RC, or OS at the different dose levels (P > .22 for all comparisons). The need for reactive gastrostomy tube (PEG) placements was significantly lower in patients receiving lower doses, 4.4% and 19.5% (P < .01). There were 14 (4.9%) grade 3 late effects in the 69.3 Gy arm compared to 1.1% in the <69.3 Gy; however, this was not statistically significant (P Z .32). Conclusion: Mild de-escalation of doses to the primary tumor and elective neck does not appear to adversely affect LRC, RC, or OS in patients with AJCC 8 th edition I-III HPV-related OPSCC, which remained true after stratification. Patients treated with lower doses had significantly reduced PEG tube rates compared to those in the highdose group.